Antineoplastic agents, used for treatment of solid cancers such as lung cancer or digestive organ carcinomas and blood cancers such as leukemia, are systemically administered through routes of administration such as intravenous or oral administration, and then, are distributed to specific tumorous sites and inhibit or suppress the proliferation of cancer cells to exhibit their therapeutic efficacy. However, the systemically-administered antineoplastic agents are rapidly taken into livers and reticuloendothelial organs from blood, or rapidly excreted into urine, and accordingly, their blood concentrations may sometimes be lowered to allow the distribution into tumorous sites to be insufficient. In addition, common antineoplastic agents themselves have poor distribution-selectivity to tumorous sites (tumor selectivity), and therefore, the antineoplastic agents are uniformly distributed over various tissues and cells of the whole body, and act as cytotoxins also against normal cells and tissues, which results in problems of the appearance of adverse effects, e.g., emesis, pyrexia, or alopecia at an extremely high rate. Therefore, it has been desired to develop a means of efficiently and selectively distributing antineoplastic agents to tumorous sites.
As one of such means, a process was proposed in which an antineoplastic agent is bound to a polysaccharide polymer to delay the disappearance of the antineoplastic agent from blood and to enhance selectivity to tumor tissues. For example, Japanese Patent Publication (KOKOKU) No. (Hei) 7-84481/1995 discloses a drug complex in which daunorubicin, doxorubicin, mitomycin C, bleomycin or the like is introduced into a carboxymethylated mannoglucan derivative by means of a Schiff base or an acid amide bond. As the mannoglucan derivative in the invention, carboxymethylated mannoglucan polyalcohols are also used. However, mannoglucan derivatives are too much branched and have complicated structures, and accordingly, it has been difficult to obtain a product with uniform quality suitable for manufacturing medicaments.
In addition, International Patent Publication WO94/19376 discloses a drug complex in which a peptide chain (the number of amino acid residues: 1 to 8) is bound to a carboxyl group of a polysaccharide having carboxyl groups, and doxorubicin, daunorubicin, mitomycin C, bleomycin or the like is further bound by means of the peptide chain. As the polysaccharide having carboxyl groups, examples are given such as polysaccharides inherently having carboxyl groups in their structures (e.g., hyaluronic acid), and polysaccharides inherently having no carboxyl groups in their structures (e.g., pullulan, dextran, chitin, etc.) in which their hydroxyl groups are modified with carbonyl groups by introducing with carboxy(C1-4)alkyl groups or binding with a polybasic acid such as malonic acid or succinic acid by esterification. The drug complexes are structurally characterized in that a drug such as doxorubicin and the above-mentioned polysaccharide moiety are bound to each other by means of a spacer, and the complexes have higher antineoplastic activity compared to doxorubicin and reduced toxicity and adverse effects.
As for technologies relating to drug complexes utilizing polyalcoholized polysaccharide derivatives as drug delivery carriers, some reports are available, for example, “Researches on polysaccharide-peptide-doxorubicin complexes—Correlations between stabilities of polysaccharide carriers in blood and their anti-neoplastic activities” (Abstracts of 10th Meeting of the Japan Society of Drug-Delivery System, 279, 1994); “Researches on polysaccharide-peptide-doxorubicin complexes—Pharmacokinetics and anti-neoplastic activity” (Abstracts of 9th Annual Meeting of Japanese Society for the study of xenobiotics, 292, 1994); Abstracts of 19th Seminar of Trends in Research and Development (held by The Organization for Drug ADR Relief, R&D Promotion and Product Review), D-9, 1995; and “Researches on drug delivery to a tumor tissue by polysaccharide carriers” (Abstracts of 12th Colloid and Interface